Computational models of normal liver function and xenobiotic induced liver damage are increasingly being used to interpret in vitro and in vivo data and as an approach to the de novo prediction of ...the liver's response to xenobiotics. The microdosimetry (dose at the level of individual cells) of xenobiotics vary spatially within the liver because of both compound-independent and compound-dependent factors. In this paper, we build model liver lobules to investigate the interplay between vascular structure, blood flow and cellular transport that lead to regional variations in microdosimetry. We then compared simulation results obtained using this complex spatial model with a simpler linear pipe model of a sinusoid and a very simple single box model. We found that variations in diffusive transport, transporter-mediated transport and metabolism, coupled with complex liver sinusoid architecture and blood flow distribution, led to three essential patterns of xenobiotic exposure within the virtual liver lobule: (1) lobular-wise uniform, (2) radially varying and (3) both radially and azimuthally varying. We propose to use these essential patterns of exposure as a reference for selection of model representations when a computational study involves modeling detailed hepatic responses to xenobiotics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication ...from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (α), conversion of healthy to stressed cells (β) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/β (fast proliferation), combined with a large γ/β (slow death) have the lowest probabilities of tissue survival. At large α/β, tissue fate can be described by a critical γ/β* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The correlation of phenotypic outcomes with genetic variation and environmental factors is a core pursuit in biology and biomedicine. Numerous challenges impede our progress: patient phenotypes may ...not match known diseases, candidate variants may be in genes that have not been characterized, model organisms may not recapitulate human or veterinary diseases, filling evolutionary gaps is difficult, and many resources must be queried to find potentially significant genotype-phenotype associations. Non-human organisms have proven instrumental in revealing biological mechanisms. Advanced informatics tools can identify phenotypically relevant disease models in research and diagnostic contexts. Large-scale integration of model organism and clinical research data can provide a breadth of knowledge not available from individual sources and can provide contextualization of data back to these sources. The Monarch Initiative (monarchinitiative.org) is a collaborative, open science effort that aims to semantically integrate genotype-phenotype data from many species and sources in order to support precision medicine, disease modeling, and mechanistic exploration. Our integrated knowledge graph, analytic tools, and web services enable diverse users to explore relationships between phenotypes and genotypes across species.
Purpose To characterize the optical coherence tomography (OCT) angiography, en face OCT, and microperimetry features of paracentral acute middle maculopathy in both the acute phase and after ...resolution, and to propose a classification of distinct subtypes of this entity. Design Retrospective observational case series. Methods Clinical histories, high-resolution digital color imaging, spectral-domain OCT images, fluorescein angiography, OCT angiography images, and en face OCT images of 16 patients with paracentral acute middle maculopathy were evaluated. Microperimetry was available in 6 patients. Results The most common referring diagnoses were isolated branch retinal arterial occlusion (5/16), combined central retinal vein and cilioretinal artery occlusion (4/16), and isolated central retinal vein occlusion (4/16). All patients demonstrated hyperreflective plaque-like lesions at the level of the inner nuclear layer on spectral-domain OCT, with no fluorescein angiographic correlate. OCT angiography demonstrated variable areas of capillary dropout within the superficial and deep retinal capillary plexi in these areas. En face OCT highlighted confluent areas of middle retina hyperreflectivity corresponding to these lesions. Three distinct en face OCT patterns were observed: arteriolar, fern-like, and globular. Microperimetry demonstrated relative scotomas mapping to the area of middle retinal hyperreflectivity seen on en face OCT. Conclusions Paracentral acute middle maculopathy may be best evaluated with the use of en face OCT imaging, which corresponds to subjective and objective visual field defects. En face OCT appearance may be used to classify paracentral acute maculopathy into distinct subtypes.
Objective:
The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients.
Background:
Blood component therapy ...(BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality.
Methods:
We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications.
Results:
A total of 1623 WB: 1180 (74%), BCT: 443(27%) patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all
P
<0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients (
P
<0.0001).
Conclusions:
Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.
We sought to investigate the risk of cataract development among patients with juvenile idiopathic arthritis (JIA)-associated uveitis treated with topical corticosteroids.
Retrospective cohort study.
...We included 75 patients with JIA-associated uveitis observed from July 1984 through August 2005 at a single academic center.
Clinical data on these patients were collected by chart review and were analyzed.
Incidence of new-onset cataract. Risk factors for cataract development were assessed with attention paid to the use of topical corticosteroids.
Over a median follow-up of 4 years, the incidence of new-onset cataract was 0.04/eye-year (EY; 95% confidence interval CI, 0.02-0.09). Of the 60 eyes in 40 patients who received topical corticosteroid therapy, there was a dose-dependent increase in the rate of cataract development among eyes receiving topical corticosteroids. The incidence of cataract was 0.01/EY for eyes treated with <3 drops daily and 0.16/EY (P = 0.0006 for log-rank test) for eyes treated with >3 drops daily. Among eyes receiving <2 drops daily, the incidence of cataract was 0/EY (95% CI 1 sided, 0.03/EY). Presence of posterior synechiae, active uveitis, and use of topical corticosteroids at presentation were significantly associated with cataract development after controlling for confounding variables. Use of topical corticosteroids was associated with cataract formation independent of uveitis activity. Using longitudinal data analysis and controlling for duration of uveitis, presence and degree of active uveitis, and concomitant use of other forms of corticosteroids in a time-updated fashion, treatment with <3 drops daily of topical corticosteroid was associated with an 87% lower risk of cataract formation compared with eyes treated with >3 drops daily (relative risk, 0.13; 95% CI, 0.02-0.69; P = 0.02).
In our cohort, topical corticosteroid use was associated with an increased risk of cataract formation independent of active uveitis or presence of posterior synechiae. However, chronic use of topical corticosteroids dosed at <3 drops daily seemed to be associated with a lower risk of cataract development relative to eyes receiving higher doses over follow-up in the setting of suppressed uveitis.
Proprietary or commercial disclosure may be found after the references.
We sought to investigate the risk of cataract development among patients with juvenile idiopathic arthritis (JIA)-associated uveitis treated with topical corticosteroids.
Retrospective cohort study.
...We included 75 patients with JIA-associated uveitis observed from July 1984 through August 2005 at a single academic center.
Clinical data on these patients were collected by chart review and were analyzed.
Incidence of new-onset cataract. Risk factors for cataract development were assessed with attention paid to the use of topical corticosteroids.
Over a median follow-up of 4 years, the incidence of new-onset cataract was 0.04/eye-year (EY; 95% confidence interval CI, 0.02-0.09). Of the 60 eyes in 40 patients who received topical corticosteroid therapy, there was a dose-dependent increase in the rate of cataract development among eyes receiving topical corticosteroids. The incidence of cataract was 0.01/EY for eyes treated with < or = 3 drops daily and 0.16/EY (P = 0.0006 for log-rank test) for eyes treated with >3 drops daily. Among eyes receiving < or = 2 drops daily, the incidence of cataract was 0/EY (95% CI 1 sided, 0.03/EY). Presence of posterior synechiae, active uveitis, and use of topical corticosteroids at presentation were significantly associated with cataract development after controlling for confounding variables. Use of topical corticosteroids was associated with cataract formation independent of uveitis activity. Using longitudinal data analysis and controlling for duration of uveitis, presence and degree of active uveitis, and concomitant use of other forms of corticosteroids in a time-updated fashion, treatment with < or = 3 drops daily of topical corticosteroid was associated with an 87% lower risk of cataract formation compared with eyes treated with >3 drops daily (relative risk, 0.13; 95% CI, 0.02-0.69; P = 0.02).
In our cohort, topical corticosteroid use was associated with an increased risk of cataract formation independent of active uveitis or presence of posterior synechiae. However, chronic use of topical corticosteroids dosed at < or = 3 drops daily seemed to be associated with a lower risk of cataract development relative to eyes receiving higher doses over follow-up in the setting of suppressed uveitis.
Proprietary or commercial disclosure may be found after the references.
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